In contrast to HIV-1 infection of humans and SIV infection of rhesus macaques (RMs), which are almost invariably associated with AIDS, natural lentiviral infections of African primates, such as SIVsmm infection of sooty mangabeys (SM), are typically non-pathogenic. The mechanisms underlying this non-pathogenic phenotype remain largely unknown; however, we have previously shown that a key feature of nonpathogenic SIV infection is the absence of chronic, generalized immune activation in the context of low cellular immune responses to the virus. As the HIV-associated immune activation (IA) is thought to be a key factor in the pathogenesis of AIDS, we proposed that the lack of IA protects SIV-infected SMs from disease progression. In further studies, we observed that SM-derived plasmacytoid dendritic cells (pDCs) produce significantly lower levels of type 1 interferon (IFNs) in response to toll-like receptor (TLR)-7 or -9 stimulation than human or RM-derived pDCs. These findings led us to hypothesize that a blunted type 1 IFN responses to TLR-7/9 stimulation mediated by SIV or its products protects SIV-infected SMs from developing the generalized immune activation associated with pathogenic HIV/SIV infections. The aim of this project is to directly test this hypothesis by treating naturally SIV-infected SMs with IFN-a and TLR-7/-9 stimulation, as well as treating SIV-infected RMs with anti-IFN-a antibody and TLR-7/-9 inhibitors. These interventions will allow us to determine whether and to what extent differences in the level of pDCs responsiveness to TLR-7/-9 stimulation and/or IFN-a production between RMs and SMs are responsible for the striking differences in the level of immune activation observed in these two species after SIV infection. The results of these studies will improve our understanding of the mechanisms underlying the lack of disease in SIV-infected SMs and determine whether targeting TLR-7/9 activation and/or IFN-a production are promising targets for therapeutic interventions aimed at reducing the HIV-associated chronic immune activation.